Generation of a novel rodent model for DYT1 dystonia

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• 作者：Kathrin Grundmann^a ; ¹ ; ^{Kathrin.Grundmann@med.uni-tuebingen.de} ; Nicola Glö ; ckle^a ; ¹ ; Giuseppina Martella^b ; ^c ; Giuseppe Sciamanna^b ; ^c ; Till-Karsten Hauser^d ; Libo Yu^a ; Salvador Castaneda^e ; Bernd Pichler^e ; Birgit Fehrenbacher^f ; Martin Schaller^f ; Brigitte Nuscher^g ; ^h ; Christian Haass^g ; ^h ; Jasmin Hettich^a ; Zhenyu Yueⁱ ; Huu Phuc Nguyen^a ; Antonio Pisani^b ; ^c ; Olaf Riess^a ; Thomas Ott^a
• 关键词：CV ; coefficient of variation ; MSN ; medium spiny motor neurons ; EPSP ; excitatory postsynaptic potentials ; LTP ; long term potentiation ; LTD ; long term depression ; SD ; synaptic depotentiation ; LFS ; low frequency stimulation ; RMP ; resting membrane potential
• 刊名：Neurobiology of Disease
• 出版年：2012
• 期刊代码：80_09699961
• 类别：neu
• 出版时间：July, 2012
• 卷：47
• 期：1
• 页码：61-74
• 文件大小：2220 K

摘要

A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (鈭咵TorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood.

Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology.

We developed transgenic rat models harboring the full length human mutant and wildtype Tor1A gene. A complex phenotyping approach including classical behavioral tests, electrophysiology and neuropathology revealed a progressive neurological phenotype in 鈭咵TorA expressing rats. Furthermore, we were able to replicate key pathological features of torsinA associated pathology in a second species, such as nuclear envelope pathology, behavioral abnormalities and plasticity changes. We therefore suggest that this rat model represents an appropriate new model suitable to further investigate the pathophysiology of 鈭咵TorA and to test for therapeutic approaches.